Use of alanosine as a methylthioadenosine phosphorylase-selective therapy for T-cell acute lymphoblastic leukemia in vitro.

Abstract

Methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine and methionine and is deficient in a variety of cancers including T-cell acute lymphocytic leukemia (T-ALL). Previously, we reported that the MTAP gene was deleted in over 30% of T-ALL patients at both diagnosis and relapse. We now report that MTAP-primary T-ALL cells are more sensitive to the toxicity of L-alanosine, an inhibitor of de novo AMP synthesis, than are MTAP+ primary T-ALL cells. As measured by [3H]thymidine incorporation, DNA synthesis in all seven MTAP-primary T-ALL cells was inhibited by L-alanosine with a mean IC50 of 4.8+/-5.3 ILM (range, 0.3-11.3 microM). On the other hand, the IC50 for 60% (12 of 20) of MTAP+ primary T-ALL was 19+/-18 microM (range, 1.7-67 microM; P = 0.02), whereas the remaining 40% (8 of 20) had an IC50 of >80 microM4. Furthermore, normal lymphocytes and MTAP+ primary T-ALL cells were rescued from L-alanosine toxicity by the MTAP substrate 5'-deoxyadenosine, but MTAP-T-ALL cells were not. These results indicate that normal cells, which are intrinsically MTAP+, would be protected from L.-alanosine toxicity, whereas MTAP-tumor cells would be killed. Thus, our results support the use of L-alanosine alone or in combination with a salvage agent as a MTAP-selective therapy and therefore lay the foundation for the initiation of clinical trials for the treatment of T-ALL and other MTAP-deficient malignancies with L-alanosine.

• Authors: A Batova, M B Diccianni, M Omura-Minamisawa, J Yu, C J Carrera, L J Bridgeman, F H Kung, J Pullen, M D Amylon, A L Yu
• Journal: Cancer research (Cancer Res) Vol. 59 Issue 7 Pg. 1492-7 (Apr 01 1999) ISSN: 0008-5472 [Print] United States
• PMID: 10197619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• alanosine
• Adenosine Monophosphate
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase
• Alanine
• Thymidine

Topics

• Adenosine Monophosphate (biosynthesis)
• Alanine (analogs & derivatives, therapeutic use)
• Antibiotics, Antineoplastic (therapeutic use)
• Humans
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, metabolism)
• Polymerase Chain Reaction
• Purine-Nucleoside Phosphorylase (deficiency, genetics, metabolism)
• Thymidine (metabolism)